We have shown that p53 promotes aerobic metabolism through its positive regulation of mitochondrial respiration. p53 null mice, a model of de novo tumorigenesis, display profound deficiencies in aerobic exercise capacity. Remarkably, the promotion of exercise capacity by a tumor suppressor gene in a mouse model parallels the human epidemiologic observation of a strong inverse relationship between exercise capacity and cancer incidence. We hypothesized that these two independent observations may share mechanisms and that studying them will yield insights useful for developing disease prevention strategies. Specifically, we are focusing on cardiovascular and metabolic functions in individuals with Li-Fraumeni syndrome, a premature cancer syndrome caused by germline mutations in the p53 gene, with the goal of developing strategies for maintaining health. We are also examining the molecular mechanisms underlying doxorubicin induced cardiomyopathy which involves p53 and mitochondrial biogenesis.